CN106977563A - A kind of synthetic method of deuterium-labeled glucosiduronate HPR - Google Patents
A kind of synthetic method of deuterium-labeled glucosiduronate HPR Download PDFInfo
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- CN106977563A CN106977563A CN201710236451.9A CN201710236451A CN106977563A CN 106977563 A CN106977563 A CN 106977563A CN 201710236451 A CN201710236451 A CN 201710236451A CN 106977563 A CN106977563 A CN 106977563A
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H15/00—Compounds containing hydrocarbon or substituted hydrocarbon radicals directly attached to hetero atoms of saccharide radicals
- C07H15/20—Carbocyclic rings
- C07H15/203—Monocyclic carbocyclic rings other than cyclohexane rings; Bicyclic carbocyclic ring systems
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
- C07H1/00—Processes for the preparation of sugar derivatives
Abstract
The invention discloses a kind of synthetic method of deuterium-labeled glucosiduronate HPR, this method is with 4 nitrophenol D4For deuterium-labeled starting material, deuterium-labeled glucosiduronate HPR D is obtained through six-step process synthesis4.The present invention filters out optimal preparation process and reaction condition by many experiments, and whole technological design is rationally, workable, the deuterium-labeled glucosiduronate HPR that the present invention is prepared, purity is up to more than 98%, and yield is up to more than 70%, and isotope abundance>99%.The deuterium-labeled glucosiduronate HPR that the present invention is prepared can be provided for examination and control sample, with important application value as the deuterium-labeled metabolin of HPR for the metabolic mechanism research and the research of antitumor machanism of HPR.
Description
Technical field
The invention belongs to isotope marks drug metabolite synthesis technical field, and in particular to a kind of deuterium-labeled glucoside
The synthetic method of sour HPR.
Background technology
The alias of HPR has Suwei A amine, phenol dimension A amine, vitamin A acid para hydroxybenzene amine and alltrans-N- (4- oxybenzenes
Base) vitamin A acid.HPR can improve intracellular reactive oxygen level, and energy inducing in vitro human hepatocellular carcinoma cells apoptosis has
Good antitumor activity.Molecular weight is 391.55, and molecular formula is C26H33NO2, and structural formula is as follows：
Glucosiduronate HPR is a kind of interior metabolism product of HPR, it is also possible to resisted with good
Tumor promotion.Its water solubility more preferably, is more beneficial for absorbing, so action effect may be more preferably.This is accomplished by glucoside
Sour HPR carries out further clinical test.The structural formula of glucosiduronate HPR is as follows：
Deuterium-labeled glucosiduronate HPR is the compound for replacing 4 hydrogen atom D-atoms on phenyl ring.
The structural formula of deuterium-labeled glucosiduronate HPR is as follows：
Deuterium is a kind of non radioactive isotope of hydrogen, and symbol is D.The isotope abundance of deuterium is about in nature
0.016%.Deuterium-labeled compound is stable isotope labelled compound, and it is by the hydrogen atom in compound or part hydrogen atom
The compound replaced with D-atom.Deuterium-labeled compound all plays irreplaceable in biomedical, pharmacokinetics
Effect.The parameter in terms of drug-metabolic pathway, metabolic mechanism and dynamics, the supervision of U.S.'s food and medicine can for example be obtained
Pointed out in the industrial directory that management board (FDA) promulgates in new drug research, drug metabolism safety evaluation has to use isotope mark
Note technology.Isotope marks tracer technique turns into the important method that clinical medicine is metabolized in research.The master of isotope marks medicine
" analysis internal standard " and " biological internal standard " are functioned as, it has very big application value in drug metabolite research.This
Applicant is on the basis of pertinent literature is consulted, and the synthetic method to deuterium-labeled glucosiduronate HPR has been carried out in detail
Research.
The country there are no the synthetic method of glucosiduronate HPR and deuterium-labeled glucosiduronate HPR
Report.
The content of the invention
The present invention solves the technical problem of there is provided a kind of synthesis of deuterium-labeled glucosiduronate HPR
Method.
Deuterium-labeled glucosiduronate HPR-D of the present invention4Synthetic route as shown in Figure 1.
Specifically, the synthetic method of the deuterium-labeled glucosiduronate HPR, comprises the following steps：
(1) with the 4- nitrophenols-D of compound 24For start mark thing, dry pyridine and acylating reagent are added, second is carried out
Acylation reaction, is made compound 3；
(2) take step (1) to prepare compound 3 in methanol, under nitrogen protection, add Pd/C catalytic hydrogenating reduction nitre
Compound 4 is made in base；
(3) compound 4 obtained by step (2) is taken to be condensed with compound 5 in aprotic solvent with condensing agent DCC, reaction
Compound 6 is made, wherein, the compound 5 is vitamin A acid；
(4) compound 6 for taking step (3) to obtain, is made compound 7 with basic hydrolysis in methyl alcohol；
(5) take the compound 7 that step (4) is prepared to be reacted with compound 8 under the conditions of lithium hydroxide and compound is made
9, wherein, the compound 8 is bromine sugar；
(6) compound 9 for taking step (5) to prepare, is made compound 1 with basic hydrolysis in methyl alcohol.
In step (1), the acylating reagent is the one or two kinds of in acetic anhydride and chloroacetic chloride.Preferably use acetic acid
Acid anhydride.
Wherein, in step (1), the acylating reagent is 0.1~10 equivalent.It is preferred that 1.75 equivalents.
In step (1), the volume ratio of the dry pyridine and acylating reagent is 4-5:1.
In step (1), the reaction condition of acetylation is：1~10h is reacted at 25~125 DEG C.
In step (2), the consumption of the methanol is 10~100 times of volumes, preferably 15-20 times volume.
In step (2), the catalyst Pd/C is 0.1~10 equivalent, preferably 0.5 equivalent.
In step (3), the condensing agent DCC is 1~10 equivalent, preferably 1.02 equivalents.
In step (3), the aprotic solvent is selected from acetonitrile, ethyl acetate, dichloromethane, tetrahydrofuran and 2- methyl four
One or more in hydrogen furans.It can be mixed when selecting a variety of with arbitrary proportion.
In step (4), the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.
In step (5), the lithium hydroxide is 0.1~10 equivalent.Preferably 1 equivalent.
In step (6), the alkali is sodium hydroxide, potassium hydroxide or lithium hydroxide.It is preferred that lithium hydroxide.
Beneficial effect：The synthesis technique of the present invention is reasonable in design, workable；The reagent used in synthetic method is simple
It is easy to get；React obtained deuterium-labeled glucosiduronate HPR, purity up to more than 98%, yield up to more than 70%,
And isotope abundance>99%.The deuterium-labeled glucosiduronate HPR that the present invention is obtained as HPR deuterium
Metabolin is marked, can be provided for the metabolic mechanism research and the research of antitumor machanism of HPR for examination and control sample,
With important application value.In addition, metabolin of the glucosiduronate HPR as HPR, it is also possible to have
More excellent antitumor activity.The synthesis of deuterium-labeled glucosiduronate HPR is easy to the later stage to important human body generation of medicine
Thank to product and its analogies carry out chemical synthesis, and its activity is studied, obtain the medicine point of more effective, less side effect
Son.
Brief description of the drawings
Fig. 1 is synthetic route of the present invention；
Fig. 2 is the nuclear magnetic spectrum of the compound 7 of embodiment 1；
Fig. 3 is the liquid chromatogram of the compound 7 of embodiment 1；
Fig. 4 is the mass spectrogram of the compound 7 of embodiment 1；
Fig. 5 is the nuclear magnetic spectrum of the compound 1 of embodiment 1；
Fig. 6 is the liquid chromatogram for the compound 1 that embodiment 1 is synthesized；
Fig. 7 is the mass spectrogram of the compound 1 of embodiment 1；
Fig. 8 be embodiment it is 2-in-1 into compound 1 liquid chromatogram.
Embodiment
Following embodiment is only that the detailed description present invention, is not intended to limit the present invention.
Reagent source：
4- nitrophenols-D4Purchased from Canadian C/D/N Isotopes Inc.
Embodiment 1
The preparation of compound 3：
Into 100ml round-bottomed flask, 4- nitrophenols-D is sequentially added4(2.25g, 15.7mmol), 16.9ml
Dry pyridine and 3.94ml acetic anhydrides, reaction are warming up to 90 degree of oil bath and stirred 2 hours, and reaction solution is in brown.TLC shows that raw material is anti-
Should completely after, be cooled to room temperature (18 degree), be spin-dried for pyridine, add 20ml water, stirring, a large amount of solids of precipitation, suction filtration, with appropriate
Water washing, is drained, and it is dried overnight to be put into vacuum desiccator, obtains product Compound 3 (2.88g, pale solid).Yield
98.95%.
The preparation of compound 4：
Preparation gained compound 3 (2.88g, 15.5mmol), 43.2ml first are sequentially added into a 100ml round-bottomed flask
Alcohol, raw material is less soluble, weighs and add successively under nitrogen protection 0.43g Pd/C, the logical hydrogen of reaction, under room temperature (18 degree)
React 1.5h.TLC shows after raw material reaction completely that suction filtration, is washed, filtrate is spin-dried for appropriate methanol, obtained under nitrogen protection
To crude product 2.36g.Crude product crosses post purification and obtains compound 4 (1.9g, white solid).Yield 78.72%.
The preparation of compound 6:
Compound 4 obtained by above-mentioned preparation is sequentially added into a 100ml round-bottomed flask, and (1.9g uses dry THF 10ml
× 2 bands are dry, and oil pump is drained), 28.5ml dry methylene chlorides, dissolution of raw material, in water white transparency, compound 5 is added into reaction
(vitamin A acid) (3.75g, 12.4mmol), reaction is changed into the turbid shape of yellow, adds DCC (2.58g, 12.4mmol) and DMAP
(0.19g, 1.59mmol), reaction is changed under brown color, room temperature (18 degree), is stirred overnight.TLC shows that raw material has almost reacted
Entirely.Processing, about 80ml saturations NaHCO is added into reaction solution3The aqueous solution, is extracted with ethyl acetate (50ml × 3), anhydrous
Na2SO4Dry, filtering is spin-dried for.Obtain crude product cross post purification obtain product Compound 6 (4.6g, yellow solid).Yield
85.8%.
The preparation of compound 7:
Compound 6 (2.6g, 5.9mmol) is sequentially added into a 500ml round-bottomed flask, 91ml methanol, raw material is difficult
It is molten, 5.9ml NaOH (1N) are added, still have part material insoluble, 90ml methanol is added, raw material all dissolves, and reaction solution is in pale brown
Color clarifies shape, (18 degree) reaction 10min of room temperature.TLC shows that raw material reaction is complete.Processing, reaction moves to ice bath, adds 3N HCl
PH=5 is adjusted, methanol is spin-dried for, about 50ml water is added, is extracted with ethyl acetate (50ml × 3), anhydrous Na2SO4Dry, filter, rotation
It is dry, obtain the used post purification of crude product and obtain product Compound 7 (2.3g, yellow solid).To compound 7 survey nuclear-magnetism, liquid phase and
Mass spectrum, as a result such as Fig. 2, Fig. 3 and Fig. 4, wherein, HPLC 99.5%, MS is correct, yield 97.86%.
1H NMR(300MHz,CDCl3):δ1.033(s,6H),1.56(m,2H),1.62(m,2H),1.71(s,3H),2.0
(m, the 2H) .MS of~2.1 (m, 5H), 2.41 (s, 3H), 4.96 (s, 1H), 5.77 (s, 1H), 6.1~6.4 (4H), 6.9~1.1:
396.0[M+H]+。
The preparation of compound 9:
Compound 7 (0.44g) is added into 10ml round-bottomed flask, 2.2ml methanol, raw material is not dissolved.Add
Lithium hydroxide monohydrate (45 milligrams), is stirred 1 hour.Compound 8 (bromine sugar) (0.44g) is added, it is small that reaction is stirred at room temperature 1
When, point plate reaction is complete, with second acid for adjusting pH to 7, is spin-dried for reaction solution and obtains crude product, crosses pillar and purify to obtain compound 9
(0.69g), yield 87.6%.
The preparation of compound 1:
Compound 9 (0.19g), methanol (4ml) and lithium hydroxide monohydrate (60 are added to 10ml round-bottomed flask
Milligram).Reaction room temperature is stirred (10 degree) and mixed overnight.TLC display reactions are complete.Reaction solution is spin-dried for, is added water, pH=6 is adjusted with acetic acid,
Separate out solid, suction filtration it is dry 1 0.13 grams of compound.Nuclear-magnetism, liquid phase and mass spectrum are surveyed to compound 1, as a result such as Fig. 5, Fig. 6 and
Fig. 7, it is seen that HPLC (98.05%), is shown in accompanying drawing 6, and MS is correct, yield 85.8%.
1H NMR(300MHz,DMSO-d6):δ 1.0 (5H), 1.45~1.60 (4H), 3.0~3.2 (3H), 4.75 (d,
1H), 4.97 (s, 1H), 5.22 (s, 1H), 6.0 (s, 1H), 6.1~6.4 (4H), 6.9 (m, 1H), 7.3 (1H), 9.9 (brs,
1H).MS:570.1[M-H]-.
Embodiment 2
The preparation of compound 3：
Into 100ml round-bottomed flask, 4- nitrophenols-D is sequentially added4(3g, 20.9mmol), 30ml dry pyrrole
Pyridine and 6ml acetic anhydrides, reaction are warming up to 100 degree of oil bath and stirred 1 hour, and reaction solution is in brown.TLC shows that raw material reaction is complete
Afterwards, room temperature (20 degree) is cooled to, pyridine is spin-dried for, 50ml water is added, stirring separates out a large amount of solids, suction filtration, with appropriate washing
Wash, drain, it is dried overnight to be put into vacuum desiccator, obtains product Compound 3 (3.0g, pale solid).Yield 77.30%.
The preparation of compound 4：
Preparation gained compound 3 (3g, 16.2mmol) is sequentially added into a 150ml round-bottomed flask, 60ml methanol is former
Material is less soluble, weighs and add successively under nitrogen protection 0.6g Pd/C, and the logical hydrogen of reaction reacts 1h under room temperature (20 degree).
TLC shows after raw material reaction completely that suction filtration, is washed, filtrate is spin-dried for appropriate methanol, obtain crude product under nitrogen protection
2.4g.Crude product crosses post purification and obtains compound 4 (1.85g, white solid).Yield 73.58%.
The preparation of compound 6:
Compound 4 obtained by above-mentioned preparation is sequentially added into a 100ml round-bottomed flask, and (1.85g uses dry THF 15ml
× 2 bands are dry, and oil pump is drained), 27.7ml dry methylene chlorides, dissolution of raw material, in water white transparency, compound 5 is added into reaction
(vitamin A acid) (3.65g, 12.1mmol), reaction is changed into the turbid shape of yellow, adds DCC (3.68g, 17.8mmol) and DMAP
(0.189g, 1.54mmol), reaction is changed under brown color, room temperature (20 degree), is stirred overnight.TLC shows that raw material has almost reacted
Entirely.Processing, about 90ml saturations NaHCO is added into reaction solution3The aqueous solution, is extracted with ethyl acetate (60ml × 3), anhydrous
Na2SO4Dry, filtering is spin-dried for.Obtain crude product cross post purification obtain product Compound 6 (3.4g, yellow solid).Yield
65.17%.
The preparation of compound 7:
Compound 6 (3.4g, 7.7mmol) is sequentially added into a 500ml round-bottomed flask, 200ml methanol, raw material is difficult
It is molten, 7.7ml NaOH (1N) are added, still have part material insoluble, reaction solution clarifies shape, (20 degree) reactions of room temperature in brown color
20min.TLC shows that raw material reaction is complete.Processing, reaction moves to ice bath, adds 3N HCl regulation pH=5, is spin-dried for methanol, adds
About 80ml water, is extracted, anhydrous Na with ethyl acetate (80ml × 3)2SO4Dry, filtering is spin-dried for, obtain the used post purification of crude product
Obtain product Compound 7 (2.0g, yellow solid).Yield 65.07%.Nuclear-magnetism is identical with the compound 7 synthesized in example 1.
The preparation of compound 9:
Compound 7 (2g) is added into 10ml round-bottomed flask, 20ml methanol, raw material is not dissolved.Add hydrogen-oxygen
Change lithium monohydrate (0.2 gram), stir 2 hours.Compound 8 (bromine sugar) (2.0g) is added, reaction is stirred overnight at room temperature, and point plate is anti-
Should be complete, with second acid for adjusting pH to 7, it is spin-dried for reaction solution and obtains crude product, crosses pillar and purify to obtain compound 9 (1.8g), yield
50.3%.
The preparation of compound 1:
Compound 9 (1.8g), methanol (40ml) and lithium hydroxide monohydrate are added to 250ml round-bottomed flask
(60 milligrams).Reaction room temperature is stirred (10 degree) and mixed overnight.TLC display reactions are complete.Reaction solution is spin-dried for, is added water, second acid for adjusting pH is used
=6, separate out solid, suction filtration it is dry 1 1.1 grams of compound.HPLC (99.09%), is shown in accompanying drawing 8, and MS is correct, yield 76.6%.
Nuclear-magnetism is identical with the compound 1 synthesized in example 1.
Claims (9)
1. a kind of synthetic method of deuterium-labeled glucosiduronate HPR, it is characterised in that comprise the following steps：
(1) with the 4- nitrophenols-D of compound 24For start mark thing, dry pyridine and acylating reagent are added, acetylation is carried out anti-
Should, compound 3 is made,
(2) take step (1) to prepare compound 3 in methanol, under nitrogen protection, add Pd/C catalytic hydrogenating reduction nitro systems
Compound 4 is obtained,
(3) take the compound 4 obtained by step (2) to be condensed with compound 5 in aprotic solvent with condensing agent DCC, chemical combination is made
Thing 6, wherein, the compound 5 is vitamin A acid,
(4) compound 6 for taking step (3) to obtain, is made compound 7 with basic hydrolysis in methyl alcohol,
(5) take the compound 7 that step (4) is prepared to be reacted with compound 8 under the conditions of lithium hydroxide and compound 9 is made, its
In, the compound 8 is bromine sugar；
(6) compound 9 for taking step (5) to prepare, is made compound 1 with basic hydrolysis in methyl alcohol,
2. synthetic method according to claim 1, it is characterised in that in step (1), the reagent used in the acetylation is
One or two kinds of in acetic anhydride and chloroacetic chloride.
3. synthetic method according to claim 1, it is characterised in that in step (1), the reaction condition of acetylation is：
1~10h is reacted at 25~125 DEG C.
4. synthetic method according to claim 1, it is characterised in that in step (2), the consumption of the methanol is 10~
100 times of volumes；The catalyst Pd/C is 0.1~10 equivalent.
5. synthetic method according to claim 4, it is characterised in that in step (2), the consumption of the methanol is 15 times of bodies
Product；The catalyst Pd/C is 1.75 equivalents.
6. synthetic method according to claim 1, it is characterised in that in step (3), the aprotic solvent is selected from second
One or more in nitrile, ethyl acetate, dichloromethane, tetrahydrofuran and 2- methyltetrahydrofurans.
7. synthetic method according to claim 1, it is characterised in that in step (3), the condensing agent DCC works as 1~10
Amount.
8. synthetic method according to claim 1, it is characterised in that in step (5), the lithium hydroxide is 0.1~10
Equivalent, preferably 1 equivalent.
9. synthetic method according to claim 1, it is characterised in that in step (4) and step (6), the alkali is hydrogen-oxygen
Change sodium, potassium hydroxide or lithium hydroxide.
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